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Genetics - Potocki Lupski

Houston, Texas

BCM pediatricians care for children in various clinical and hospital environments.
Potocki-Lupski Syndrome - Department of Molecular and Human Genetics
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About Potocki-Lupski (dup17p11.2) Syndrome

Individuals with the genetic condition designated as dup(17)(p11.2p11.2) (OMIM #610883), or dup 17p carry extra genetic information (known as a duplication) on the short arm of chromosome 17.

Each cell of the body should have 23 pairs of chromosomes (22 numbered chromosomes and one pair of sex chromosomes; XX for females and XY for males) that contain the complete genetic information (genome) for the individual. When the egg and sperm cells are formed, the pairs of chromosomes are separated in a process called meiosis, so that each egg or sperm contains only one copy of each chromosome. Errors that occur during this process can result in genomic imbalances such as missing or extra genetic material. These imbalances can cause genetic syndromes that are associated with a wide variety of clinical outcomes.

Many genetic syndromes that were first described on the basis of clinical findings were later found to be caused by genomic imbalances. New high-resolution laboratory tests—known as chromosomal microarray analysis or CMA can now detect these genomic imbalances even when a particular syndrome is not suspected.

Two distinct conditions result from errors in meiotic recombination involving the short arm of chromosome 17:

Smith-Magenis Syndrome

Smith-Magenis syndrome (SMS – OMIM #182290) is caused by a deletion, or loss of genetic material, on one copy of chromosome 17. This well-known syndrome is associated with developmental delay, mental retardation, congenital anomalies such as heart and kidney defects, and neurobehavioral abnormalities such as severe sleep disturbances and self-injurious behavior.

For every chromosomal deletion, there exists a reciprocal chromosomal duplication. Although the genomic mechanism for the deletion and duplication is the same, the clinical features of individuals are different. These duplication syndromes have their own distinct clinical features and should not be confused with the deletion syndromes.

Potocki-Lupski Syndrome (PTLS)

Duplication of chromosome 17p11.2 – Potocki-Lupski syndrome (PTLS) (OMIM #610883) is a newly recognized genetic condition with only a few dozen cases reported in the medical literature. Patients who have this duplication often have low muscle tone, poor feeding, and failure to thrive during infancy, and also present with delayed development of motor and verbal milestones. Many individuals who have PTLS have difficulty with articulation and language processing. In addition, patients may have behavioral characteristics similar to those seen in persons with autism or autism-spectrum disorders. Individuals with PTLS may have heart defects and sleep apnea. The facial features observed in PTLS are subtly similar between individuals but are not usually described as abnormal or striking by physicians.

While fewer than 50 persons with duplication 17p11.2 have been described in the medical literature, we know that this duplication is predicted to be observed in at least 1 in 20,000 individuals. Although PTLS is considered a “chromosomal” disorder, diagnosis is often missed on a routine chromosome analysis. Due to technological advances in cytogenetics, specifically the use of array comparative genomic hybridization (aCGH) for genetic diagnosis, microdeletions and microduplications can be detected with equal fidelity. Hundreds of chromosome segments can be analyzed at one time searching for chromosomal imbalances. We anticipate that many more individuals will be diagnosed with dup 17p11.2 as this testing is performed more routinely in persons with developmental delay, mental retardation, and/or autism spectrum disorder.

While most people with PTLS have a duplication only within the 17p11.2 region, some PTLS patients have a larger duplication that extends to the Charcot-Marie-Tooth (CMT) region of 17p12 and includes the PMP22 gene. The array comparative genomic hybridization test can detect whether or not a person is duplicated for PMP22. An individual with a larger duplication that includes PMP22 will also have CMT type 1A which affects the peripheral nervous system, and is the most common type of CMT. The CMT Association is an excellent resource.

Scientific Publications

  1. Carter RD, Raia M, Ewing-Cobbs L, Gambello M, Hashmi SS, Peterson SK, Robbins-Furman P, Potocki L (2013). Stress and well-being among parents of children with potocki-lupski syndrome. J. Genet. Couns. 22(5): 633-42.
  2. Yusupov R, Roberts AE, Lacro RV, Sandstrom M, Ligon AH. Potocki-Lupski syndrome: An inherited dup(17)(p11.2p11.2) with hypoplastic left heart. Am. J. Med. Genet. A. 2011 Feb; 155(2):367-71.
  3. Sanchez-Valle A, Pierpont ME, Potocki L. The severe end of the spectrum: Hypoplastic left heart in Potocki-Lupski syndrome. Am. J. Med. Genet. A. 2011 Feb; 155(2): 363-6.
  4. Soler-Alfonso C, Motil KJ, Turk CL, Robbins-Furman P, Friedman EM, Zhang F, Lupski JR, Fraley JK, Potocki L. Potocki-Lupski Syndrome: A Microduplication Syndrome Associated with Oropharyngeal Dysphagia and Failure to Thrive. J. Pediatr. 2010 Dec 16. [Epub ahead of print]
  5. Ricard G, Molina J, Chrast J, Gu W, Gheldof N, Pradervand S, Schütz F, Young JI, Lupski JR, Reymond A, Walz K. Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models. PLoS Biol. 2010 Nov 23; 8(11): e1000543.
  6. Zhang F, Potocki L, Sampson JB, Liu P, Sanchez-Valle A, Robbins-Furman P, Navarro AD, Wheeler PG, Spence JE, Brasington CK, Withers MA, Lupski JR. Identification of uncommon recurrent Potocki-Lupski syndrome-associated duplications and the distribution of rearrangement types and mechanisms in PTLS. Am. J. Hum. Genet. 2010 Mar 12; 86(3): 462-70.
  7. Treadwell-Deering DE, Powell MP, Potocki L. Cognitive and Behavioral Characterization of the Potocki-Lupski Syndrome (Duplication 17p11.2). J. Dev. Behav. Pediatr. 2010 Jan 27.
  8. Carmona-Mora P, Molina J, Encina CA, Walz K. Mouse models of genomic syndromes as tools for understanding the basis of complex traits: an example with the smith-magenis and the potocki-lupski syndromes. Curr Genomics. 2009 Jun; 10(4): 259-68.
  9. Molina J, Carmona-Mora P, Chrast J, Krall PM, Canales CP, Lupski JR, Reymond A, Walz K. Abnormal social behaviors and altered gene expression rates in a mouse model for Potocki-Lupski syndrome. Hum. Mol. Genet. 2008 Aug 15; 17(16): 2486-95.
  10. Martin J, Knight SJ, Sharp AJ, Eichler EE, Hurst J, Kini U. Potocki-Lupski syndrome mimicking a connective tissue disorder. Clin. Dysmorphol. 2008 Jul; 17(3): 211-3.
  11. Doco-Fenzy M, Holder-Espinasse M, Bieth E, Magdelaine C, Vincent MC, Khoury M, Andrieux J, Zhang F, Lupski JR, Klink R, Schneider A, Goze-Martineau O, Cuisset JM, Vallee L, Manouvrier-Hanu S, Gaillard D, de Martinville B. The clinical spectrum associated with a chromosome 17 short arm proximal duplication (dup 17p11.2) in three patients. Am J Med Genet A. 2008 Apr 1; 146(7): 917-24.
  12. Girirajan S, Williams SR, Garbern JY, Nowak N, Hatchwell E, Elsea SH. 17p11.2p12 triplication and del(17)q11.2q12 in a severely affected child with dup(17)p11.2p12 syndrome. Clin. Genet. 2007 Jul; 72(1): 47-58.
  13. Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM, Glaze D, Krull K, Lee JA, Lewis RA, Mendoza-Londono R, Robbins-Furman P, Shaw C, Shi X, Weissenberger G, Withers M, Yatsenko SA, Zackai EH, Stankiewicz P, Lupski JR. Characterization of Potocki-Lupski Syndrome (dup17p11.2p11.2) and delineation of a dosage-sensitive critical interval that can convey and autism phenotype. Am. J. Hum. Genet. 2007 Apr; 80: 633-649.
  14. Yatsenko SA, Treadwell-Deering D, Krull K, Lewis RA, Glaze D, Stankiewicz P, Lupski JR, Potocki L. Trisomy 17p10-p12 due to mosaic supernumerary marker chromosome: delineation of molecular breakpoints and clinical phenotype, and comparison to other proximal 17p segmental duplications. Am. J. Med. Genet. A. 2005 Oct 1; 138(2): 175-80.
  15. Moog U, Engelen JJ, Weber BW, Van Gelderen M, Steyaert J, Baas F, Sijstermans HM, Fryns JP. Hereditary motor and sensory neuropathy (HMSN) IA, developmental delay and autism related disorder in a boy with duplication (17)(p11.2p12). Genet. Couns. 2004; 15(1): 73-80.
  16. Stankiewicz P, Park SS, Holder SE, Waters CS, Palmer RW, Berend SA, Shaffer LG, Potocki L, Lupski JR. Trisomy 17p10-p12 resulting from a supernumerary marker chromosome derived from chromosome 17: molecular analysis and delineation of the phenotype. Clin. Genet. 2001 60: 336-344.
  17. Schneider MC, Hughes CR, Forrester S, Kimonis V. Mild phenotype due to tandem duplication of l7p11.2. Am. J. Med. Genet. 2000 Oct 2; 94(4): 296-9. Review.
  18. Potocki L, Chen KS, Park SS, Osterholm DE, Withers MA, Kimonis V, Summers AM, Meschino WS, Anyane-Yeboa K, Kashork CD, Shaffer LG, Lupski JR. Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat. Genet. 2000 Jan; 24(1): 84-7.
  19. Potocki L, Chen KS, Koeuth T, Killian J, Iannaccone ST, Shapira SK, Kashork CD, Spikes AS, Shaffer LG, Lupski JR. DNA rearrangements on both homologues of chromosome 17 in a mildly delayed individual with a family history of autosomal dominant carpal tunnel syndrome. Am. J. Hum. Genet. 1999 Feb; 64(2): 471-8.
  20. Balarin MA, da Silva Lopes VL, Varella-Garcia M. A dup(17)(p11.2p11.2) detected by fluorescence in situ hybridization in a boy with Alport syndrome. Am. J. Med. Genet. 1999 Jan 15; 82(2): 183-6.
  21. Chen KS, Manian P, Koeuth T, Potocki L, Zhao Q, Chinault AC, Lee CC, Lupski JR. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat. Genet. 1997 Oct; 17(2): 154-63.
  22. Brown A, Phelan MC, Patil S, Crawford E, Rogers RC, Schwartz C. Two patients with duplication of 17p11.2: the reciprocal of the Smith-Magenis syndrome deletion? Am. J. Med. Genet. 1996 May 17;63(2):373-7. Erratum in: Am. J. Med. Genet. 1996 Oct 28; 65(3): 254.
  23. Kozma C, Meck JM, Loomis KJ, Galindo HC. De novo duplication of 17p [dup(17)(p12----p11.2)]: report of an additional case with confirmation of the cytogenetic, phenotypic, and developmental aspects. Am. J. Med. Genet. 1991 Dec 15; 41(4): 446-50.
  24. Magenis RE, Brown MG, Allen L, Reiss J. De novo partial duplication of 17p [dup(17)(p12—›p11.2)]: clinical report. Am. J. Med. Genet. 1986 Jul; 24(3): 415-20.

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